Most osteoporotic fractures occur at skeletal locations rich in cancellous (trabecular) bone. The most widely used criterion for risk assessment is bone mineral density (BMD). However, it is well known that BMD is not a satisfactory predictor of fracture risk. Indeed, there is now compelling theoretical, experimental and clinical evidence for the role of architecture as an additional predictor of the bone's mechanical competence. During the past cycles of this project we have shown both in the laboratory and in patient studies that magnetic resonance micro-imaging (mu-MRI), in conjunction with image analysis, can predict the trabecular bone's mechanical behavior and clinical outcome, respectively. In preliminary work we have conceived a new approach toward a complete quantification of cancellous bone architecture based on three-dimensional digital topological analysis and have shown that this techniques accurately describes the conversion of trabecular plates to rods, a process well known to occur during aging and, in particular, in osteoporosis. Paralleling these developments we have made significant progress in data acquisition, processing and analysis, which improved both sensitivity and precision of mu-MRI to the extent that longitudinal studies are now feasible. During the next phase of the project we propose (i) to further develop and evaluate digital topological analysis and additional structural analysis tools; (ii) to determine the precision of the mu-MRI-derived topological and scale parameters in specimens and representative patients; (iii) to assess the sensitivity of the method to detect architectural changes during early menopause in a pilot project involving women treated with estrogen and their controls; (iv) to compare sensitivity and precision of mu-MRI with DEXA and p-QCT. The overall hypothesis to be tested is that mu-MRI-based cancellous bone structural analysis is sensitive and reproducible and capable of detecting changes in cancellous bone architecture as they occur over time, either as a result of normal changes or in response to treatment. The long-term goal of the work proposed is to establish "virtual bone biopsy," analogous to physical bone biopsy, by three-dimensional architectural analysis of mu-MRI data collected in vivo, as a means to follow patients longitudinally, either as a method for assessing osteoporosis risk or for evaluating treatment efficacy.